SUMMARY/ABSTRACT Identifying and eliminating sources of persistent HIV in various tissue and compartments is a top research priority. Anatomical compartments with unique immune environments, such as the central nervous system (CNS), may play an important role in persistence of HIV infection. Unlike peripheral blood and lymphoid tissues, HIV-1 burden in brain tissue is primarily in cells of myeloid origin, such as microglia and perivascular macrophages, but accessing brain tissue is challenging. As a result, the identification and characterization of cerebral spinal fluid (CSF) markers of persistent parenchymal HIV infection are urgently needed. We recently demonstrated that CD4+ T cell-associated HIV-1 RNA is highly enriched in cells expressing CD30, and that cells expressing this marker considerably contribute to the total pool of transcriptionally active CD4+ lymphocytes in blood and gut tissue in individuals on suppressive ART. We also demonstrated that ex vivo treatment with brentuximab vedotin, an antibody-drug conjugate (ADC) that targets CD30, significantly reduces the total amount of HIV-1 DNA in peripheral blood mononuclear cells obtained from infected, ART-suppressed individuals. As a result, we studied soluble (s)CD30 levels in plasma and CSF from HIV-1-infected individuals on ART, treatment naive participants and uninfected controls. Plasma and serum sCD30 levels were higher in plasma and CSF of treatment naive, viremic individuals compared to uninfected controls. However, whereas sCD30 levels in plasma of ART-suppressed individuals were low and similar to uninfected donors, CSF sCD30 levels in suppressed participants were similar to viremic subjects. These data suggest that there may be differences in the infection environment between CNS and peripheral blood with the potential for ongoing transcriptional activity in long-lived, CNS-resident myeloid cells. We hypothesize that sCD30 is a marker for residual HIV-1 transcriptional activity in the CNS in the setting of suppressive ART, and that infected human macrophages and microglia leads to the increases in both surface expression and soluble levels of CD30. Microglia are long-lived and can respond rapidly to microbial signals in contrast to peripheral or lymphoid tissue-based lymphocytes, and infected microglia and macrophages may be a source of persistent sCD30 in the CNS. In order to further define the role of CD30 in myeloid CNS HIV persistence, our aims are to: (1) determine if sCD30 levels in cerebral spinal fluid from viremic and ART suppressed individuals correlate with measures of HIV persistence; and (2) determine if HIV infection and viral reactivation in primary human macrophages and microglia lead to increased expression of CD30. We will also test the capacity of brentuximab vedotin to target and kill CD30-expressing, HIV-infected cells in vitro. CD30 is highly restricted on healthy cells, and therefore has the potential to act as a marker of HIV persistence and is a promising target for viral eradication strategies.